T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab
| Autor: | Arindam Saha, S Satish Kumar, Pradip Nair, Swati Patel, Ravindra B. Sadashivarao, Anuja Tushar Deshchougule, H. Pai, Ramakrishnan Melarkode, Usha Bughani, Dinesh V. Palanivelu, Reshmi Nair, Enrique Montero, Rasika Venkataraman, Anshu Kuriakose |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Physiology medicine.medical_treatment Cellular differentiation T-Lymphocytes Itolizumab lcsh:Medicine Lymphocyte Activation Immune Receptors Biochemistry White Blood Cells Mice 0302 clinical medicine Animal Cells Immune Physiology Medicine and Health Sciences Lymphocytes Post-Translational Modification Phosphorylation lcsh:Science Cells Cultured Staining Innate Immune System Multidisciplinary Immune System Proteins biology T Cells ZAP70 Cell Staining Antibodies Monoclonal Neurodegenerative Diseases Cell Differentiation Flow Cytometry Cell biology Cytokine medicine.anatomical_structure Neurology Cytokines Antibody Cellular Types medicine.drug Research Article Signal Transduction Multiple Sclerosis T cell Immune Cells Immunology Research and Analysis Methods Antibodies Monoclonal Humanized Autoimmune Diseases 03 medical and health sciences medicine Animals Humans ALCAM Blood Cells T-cell receptor lcsh:R Biology and Life Sciences Proteins Correction Cell Biology Molecular Development Demyelinating Disorders T Cell Receptors 030104 developmental biology Specimen Preparation and Treatment Immune System biology.protein Clinical Immunology lcsh:Q Clinical Medicine 030215 immunology Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 7, p e0180088 (2017) |
| ISSN: | 1932-6203 |
| Popis: | CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15-35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORγT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR-mediated T cell activation. We show that Itolizumab but not its F(ab')2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases. |
| Databáze: | OpenAIRE |
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